Candidate--As a Nephrology fellow at Washington University, I have received extensive training in clinical nephrology. I have extended my Fellowship, and spent two years doing K channel research, having had no prior research experience. My goal is to eventually become an independent clinician-researcher at a major medical center. Environment--To reach this goal, I plan to work for 5 years with Dr. Colin Nichols as my mentor, to further improve my skills in patch-clamping techniques and channel kinetic analysis, along with acquiring molecular biological techniques. Didactic courses in Cellular and Molecular Biology, and Cellular Neuroscience will provide the broad theoretical background that I feel I missed by not doing a Ph.D. An advanced course in single channel analysis at SUNY Buffalo, and a 3-month-training visit with Dr. David Colquhoun, will complete the learning elements. This program will prepare me for a career as an independent clinician-scientist. Research--Inward rectifier potassium (Kir) channels have critical roles in many tissues, including key roles in insulin secretion (Kir6.2), and potassium secretion in the kidney (Kir1.1). Mutations that alter ion channel gating can cause diseases, e.g., Bartters syndrome, and diabetes. This project will investigate gating mechanisms of metabolite-regulated KATP channels, in order to create a unified kinetic model. I propose three Specific Aims, which together seek to define, non-liganded and liganded gating mechanisms, and the role of nucleotide hydrolysis through the sulfonylurea receptor. The information gained will advance understanding of basic mechanisms of ion channel gating, and will be important for the development of more specific therapies for ion channel diseases.